Modification of morphine tolerance by behavioral variables

CA Sannerud and AM Young

These experiments assessed whether the opportunity to perform a target operant in the presence of morphine would alter the development of behavioral tolerance. Morphine tolerance was assessed in rats responding under a fixed-ratio 30 schedule of food delivery. Separate groups of rats were administered 10 mg/kg of morphine either pre- or postsession for 9 weeks. The degree of drug tolerance was assessed by determining cumulative dose-response functions for morphine before, during and after chronic administration. Three to 4-fold tolerance to the rate-decreasing effects of morphine developed in rats receiving morphine presession, whereas no tolerance developed in rats receiving an equal dose of morphine postsession. Morphine sensitivity returned to initial values 4 weeks after termination of chronic administration. Eight weeks after termination of chronic administration, the drug-daily session relationship was reversed and the rats were re-exposed to 10 mg/kg of morphine for 9 additional weeks. There were fewer differences between groups receiving morphine pre- or postsession during this second chronic administration phase. During chronic administration of morphine, the dose of naloxone required to suppress response rates decreased 100-fold in rats receiving morphine presession, but only 10- fold in rats receiving morphine postsession. In contrast, chronic administration of morphine did not alter the rate-decreasing effects of the nonopioids d-amphetamine, ketamine or pentobarbital. These experiments suggest that reinforcement of an operant response in the presence of morphine promoted the development of pharmacologically specific behavioral tolerance to morphine.

Volume 237, Issue 1, pp. 75-81, 04/01/1986
Copyright © 1986 by American Society for Pharmacology and Experimental Therapeutics